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Increased CPA6 promoter methylation in focal epilepsy and in febrile seizures
1. INCREASED CPA6 PROMOTER
METHYLATION IN FOCAL
EPILEPSY AND IN
FEBRILE SEIZURES
Annick Salzmann, PhD
Service de Médecine Génétique (HUG)
Département de Psychiatrie (UNIGE)
7ème Journée de la Recherche Clinique
8 mai 2014
3. EPILEPSY
• Chronic neurological disorder à affects all ages
• Defined by 2 or more unprovoked seizures
• 50 million people worldwide (WHO 2009)
• 0.5–1% world population
• Epileptic phenomenen
‣ Hyperexcitability & Hypersynchrony
4. FOCAL EPILEPSY
• Most common form of epilepsy (60%)
• Localisation-related – Temporal lobe epilepsy
• Resistance to anti-epileptic drugs
• Surgical resection of anterior temporal lobe structures
• Antecedent of febrile seizures
• Complex disorder = genetic + environment
5. FEBRILE SEIZURES
• Not considered to be an epileptic condition
• Provoked by fever (>38.5°)
• Prevalence: 2–5%
• Onset age: 3 months and 5 years
• Epilepsy occurs 2–10 times more
• Important genetic predisposition
6.
7. CONSANGUINEOUS FAMILY
7
Complex Febrile Seizures + Temporal Lobe Epilepsy
Complex Febrile Seizures
One Simple Febrile Seizure
Several Simple Febrile Seizures
1 2
5
3 4 5 6
4
II
III
1 2 3 6 7 8 9 10
I
M/– M/–
M/– M/–
Founder mutation = M
M/M M/M M/M M/MM/–
or
–/–
M/–
or
–/–
M/–
or
–/–
M/–
or
M/M
Common
Ancestor
Autosomal Recessive Model
9. CARBOXYPEPTIDASE A6 (CPA6)
• Member of the M14 metallocarboxypeptidase family
• Highly expressed in human embryonic brain and in fetal
umbilical cord blood (Wei et al., J. Biol. Chem. 2002)
• 50-kDa pro-CPA6 → 37-kDa active form secreted into the
extracellular matrix (Lyons et al., J. Biol. Chem. 2008)
• Cleaves C-terminal hydrophobic residues → role in
neuropeptides regulation (Lyons et al., J. Biol. Chem. 2008)
10.
11. CPA6 MUTATIONS IN
EPILEPTIC PATIENTS
CPA6 Protein
7 missense variants
Consanguineous
FEB11/ELT5 family
c.809C>T → TT
3 FE patients
c.799G>A → GA1 TLE patient
c.843A>G → AG
1 TLE patient
c.875C>G → CG
Association
Study
Association
Study
Association
Study
Sapio et al. J Biological Chemistry, 2012
13. EPIGENETICS
• Regulation of biological processes from conception to death
of an organism
• Mitotically and/or meiotically heritable variations in gene
functions, which are not due to changes in DNA sequence
• Essential for normal development, maintenance of cellular
homeostasis and functions of an adult organism
23. PERSPECTIVES
• In epilepsy field à Beginning of epigenetics research à A
few published studies and most related to DNA methylation
• New cohorts of patients
à Blood (DNA) collected after a first seizure
à Blood (DNA) collected after X seizures
à Comparison of DNA methylation level (EpiGenome wide)